Many genes have been proposed as putative oncogenes, e.g., due to their effects in experimental systems. However, a significant challenge of molecular oncology is to establish whether and how these putative oncogenes play a role in naturally occurring malignancies.
Notch genes encode heterodimeric transmembrane receptors that regulate differentiation, proliferation and apoptosis. Mammals have four known Notch genes, Notch 1-4.
Notch genes have been implicated as oncogenes in several experimental models of carcinogenesis 4-7,9. For example, it has been reported that Notch is upregulated in Ras transformed cells8. It has also been shown that aberrant Notch proteins resulting from MMTV insertional mutation or from transgenic overexpression can profoundly impair the normal mammary gland morphogenesis in mice and promote the rapid development of poorly differentiated adenocarcinomas4,11.
However, although deregulated expression of the wild type Notch protein has been described in certain cancers8, no genetic lesion of the Notch locus has been described, with the exception of a rare translocation in T cell malignancies10.
In view of the importance of finding new markers and therapeutic targets for the assessment and treatment of cancer, there is a continuing need to characterise whether and how signalling pathways are altered in spontaneously occurring tumours.
In additional, a significant amount of work has been carried out in the art to identify “cancer signatures”, which can be used in patient management or which can identify the targets subverted in neoplasia. These efforts are mainly concentrated on unbiased screening of cancer transcriptomes. For example, one approach is to identify genes whose expression is significantly modified in tumours as compared to normal cells, or in tumours of different grades (e.g., Beer et al, Nature Medicine Vol. 8, No. 8, 816-824, 2002) and to select from these a subset which are associated with survival. A difficulty of this approach is that the resultant signatures often represent the end point of complex upstream interactions, and cannot readily be allocated to particular molecular pathways.
Another approach has been used in Brown PO et al (PloS Biol. Feb. 2, 2004(2)). Here, gene expression profiles were obtained from fibroblasts, in response to serum exposure. Genes which formed part of this fibroblast common serum response were found to be regulated in many human tumours. It was proposed that this is due to similarity in the molecular mechanism of cancer progression and wound healing.
Signatures produced in the prior art are often not highly robust, and often fail to provide good results from datasets that have been obtained in different clinical environments and from different patients. Additionally, prior art signatures often include a large number of genes, which increases the cost and difficulty of clinical screening in patients.
Therefore, there is also a continuing need to develop new approaches to identifying cancer signatures, so as to identify new diagnostic, prognostic or therapeutic markers.